Our exciting experimental data generated from the last several years indicate the novel role that glutamate receptors mediated neurogenic events play as a key factor in inflammatory nociceptive processes. Glutamate receptor antagonists given the spinal cord dorsal horn eliminate half of the joint swelling induced in rat inflammation models. Our recent finding that knee injections of glutamate receptor agonists increase joint blood flow, plasma/protein extravasation, joint swelling, and nerve activation intimates peripheral glutamate involvement. This may account for glutamate increases in inflamed joints in animal models and in clinic patients with active arthritis. In clinical samples, glutamate is high in joints with active arthritis and is independent of levels in the patients other joints or in the plasma. Preliminary data presented inflammatory cascades through stimulation of tumor necrosis factor (TNF-alpha) release since glutamate added to synovial cell cultures increases TNF-alpha levels detected in the culture supernatant. Together these findings led to the hypothesis for the studies proposed that glutamate receptor mediated events play a critical role in persistent nociceptive responses and initiation of inflammatory cascades. Specific Aim 1 is to determine the types of glutamate receptors in the knee joint involved in the changes in nociceptive and inflammatory parameters. Specific Aim 2 is to establish that it is the small sensory nerves innervating the knee joint that contain and contribute to the release of glutamate in the joint. Specific Aim 3 will establish that glutamate contributes to the release of the inflammatory mediator, TNF-alpha, using clonal human synovial cell cultures. Specific Aim 4 is to determine whether the glutamate receptor promoted TNFalpha release from synovial cell cultures. Specific Aim 4 is mediated by activation of glutamate- mediated NFkappaB signal transduction pathways. These studies will eventually seek mechanisms that may lead to translational approaches to abrogation of the inflammatory state through pharmacological interventions directed at glutamate receptor-mediated signal transduction pathways. These studies will utilize anatomical, behavioral, electrophysiological, biochemical, and molecular methods to examine models in some cases after stroke, these studies seek a better understanding of the interactions of neurogenic and immune processes in the hope that reversal of joint inflammation for patients is possible.